Moxifloxacin is a broad-spectrum fluoroquinolonic antibacterial agent, used for the treatment of respiratory infections (pneumonia, chronic sinusitis, chronic bronchitis) sold in form of hydrochloride by Bayer AG under the name of Avelox® and Avalox®. It is also sold by Alcon Inc. in a low dosage form for ophthalmic use under the name of Vigamox®.
Moxifloxacin, of formula (II) and having the chemical name of 3-quinolinecarboxylic, 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[(4aS,7aS)-octahydro-6H-pyrrole[3,4-b]pyridine-6-yl]-4-oxo-acid, is characterized by a fluoroquinolonic skeleton, which is common to that of two other antibiotics of the same category (Gatifloxacin and Balofloxacin) and by a side chain constituted by (4aS,7aS)-octahydro-1H-pyrrole[3,4-b]pyridine.

The fluoroquinolonic intermediate of formula (V), with the 8-methoxy group is a commercial product.

(4aS,7aS)-Octahydro-1H-pyrrole[3,4-b]pyridine, also referred to as (S,S)-2.8-Diazabycyclo[4.3.0]nonane and having CAS RN [151213-40-0] and formula (VI),
constitutes the side chain of moxifloxacin, is the key intermediate of the synthesis in that it has two chiral centers, both having an S configuration, and is optically active and levogyre. The preparation of this key intermediate is also described in patent applications MI2009A001353 and WO2010/100215 both owned by F.I.S. Fabbrica Italiana Sintetici S.p.A. These references provide, resepctively, for a process for optimising the optical resolution and a regio and stereoselective synthesis process of the bioenzymatic type.
A first synthesis process of moxifloxacin hydrochloride described in EP 550903 includes the coupling reaction between the 1-Cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinic acid of formula (V):
with the (4aS,7aS)-Octahydro-1H-pyrrole[3,4-b]pyridine intermediate of formula (VI) in the presence of a base:

Due to the low regioselectivity of the reaction, the product obtained contains the 6-isomer impurity of formula (VIII):
as greater impurity, which—being a position isomer—is difficult to separate from the product, without significantly reducing its yield.
Chromatographic purification on a silica gel column leads to similarly low yields.
WO 2008/138759 describes a process for the preparation of moxifloxacin hydrochloride monohydrate where the coupling reaction between 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinic acid of formula (V) with (S,S)-2.8-diazabycyclo[4.3.0]nonane of formula (VI) is carried out in the absence of a base and moxifloxacin is isolated as L-tartrate or fumarate or p-ditoluoyltartrate with the aim of purifying it from the greater impurity, i.e. the 6-isomer of formula (VIII). It is then converted into moxifloxacin hydrochloride.
Another synthesis process of moxifloxacin is described in WO 2005/012285 includes the reaction between the ethyl ester of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinic acid of formula (IX):

with boric acid and acetic anhydride to form an intermediate borate complex with 95% yield which is then reacted with (4aS,7aS)-Octahydro-1H-pyrrole[3,4-b]pyridine of formula (VI) with 72% yield. After this the ester and the complex are hydrolysed, and salification is carried out to give moxifloxacin hydrochloride with a 91% yield, for an overall 62% molar yield.
In WO 2008/059223 a process similar to the previous one is employed except that the complex is generated using boric acid and propionic anhydride instead of acetic anhydride.
A fourth process, described in WO 2006/134491, provides for the reaction of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinic acid of formula (V) with boron trifluoride etherate to provide a difluoroborate intermediate which is reacted with (S,S)-2.8-diazabycyclo[4.3.0]nonane of formula (VI) in presence of a base with a 92% yield providing a difluoroborate complex of moxifloxacin which is then hydrolized and salified to provide moxifloxacin hydrochloride with an overall yield ranging from 42 to 55%.
In addition, the synthesis of moxifloxacin has been conducted, as described in EP 1832587, through a process similar to the previous one, carried out via a one-pot method and including silanization before complexation through boron trifluoride.
The processes described above lead to unsatisfactory yields and require the use of toxic reagents such as boron trifluoride.
An alternative process which overcomes these problems and especially that of the 6-isomer impurity is described in the U.S. patent application Ser. No. 13/051,081 and Italian patent application MI2010A000450 both owned by F.I.S. Fabbrica Italiana Sintetici S.p.A. where magnesium salt is used for performing the coupling between the 1-Cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinic acid of formula (V) with the intermediate (4aS,7aS)-Octahydro-1H-pyrrole[3,4-b]pyridine of formula (VI) thus avoiding the formation of the 6-isomer impurity of formula (VIII).
The above-described prior art processes for the preparation of moxifloxacin in their entirety require the use of coupling between the two syntons described previously. Such coupling also requires the inherent formation of another typical well known impurity of moxifloxacin referred to as 3-quinolinecarboxylic, 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[(4aS,7aS)-1-methyloctahydro-6H-pyrrole[3,4-b]pyridine-6-yl]-4-oxo-acid, having the formula (VII):

This impurity having the number CAS 721970-37-2 was identified and published for the first time by Dr. Reddy's Laboratories Ltd., Bulk Actives Unit-III, Hyderabad, AP (India) in the Journal of Pharmaceutical and Biomedical Analysis (2004), 34(5), 1125-1129 where it is called Impurity-1. It was observed to be present in amounts above 0.1% in industrially produced moxifloxacin.
In the publication of the United States Pharmacopeia-India Private Limited (USP-India) on Chromatographia (2009), 69(9-10), this impurity referred to as Imp-1 was correctly defined as a process impurity. The samples used by USP-India to carry out the study were provided by Dr. Reddy's Laboratories Ltd. The developed HPLC method allows detecting such impurity in moxifloxacin with a 0.016% detectability limit.
This reference as well as our own experimentation confirm that the impurity of formula (VII) is a typical process impurity of moxifloxacin. Its formation appears to be due to the action of hydrofluoric acid, released during the coupling of the two syntons on the methoxy group in position 8 which releases the methyl carbocation which in turn alkylates a second moxifloxacin molecule. This impurity is particularly difficult to remove from the product using conventional re-crystallization methods.